A number of other therapies are currently under investigation for the treatment of hepatitis C, either as monotherapy or in combination with PEGASYS®. These Include various inhibitors directly targeting viral proteins such as the polymerase VX-950 (Vertex) and protease R1626 (Roche). New molecules for the treatment of hepatitis C are currently in phase I-III clinical trials. Currently there are no clinical trials with G2/3 patients. When new molecules eventually reach the market, they will most likely be given in a triple combination therapy to reduce the risk of viral resistance.
In contrast to results seen with pegylated interferon alfa-2b monotherapy, PEGASYS® has been associated with consistent and substantial viral load decline, consistent with sustained serum concentrations over the entire once-weekly dosing interval.
Telaprevir is a highly selective peptidomimetic inhibitor of the HCV NS3-4A protease that is designed to stop virus replication with a shorter treatment duration than current pegylated interferons. Telaprevir monotherapy has been shown to have substantial antiviral effects which are increased with the addition of PEGASYS®. As can be seen from the figure (below), decreases in HCV RNA are sustained with all three regimens.
Figure 3-8: New Molecules: PEGASYS® PK leads to rapid, sustained viral load decline
Recent data from Phase IIb clinical trials demonstrates that treatment of genotype 1 patients with triple combination therapy consisting of Telaprevir plus PEGASYS® and ribavirin for 24 weeks results in high SVR rates (61%). Incidently, RVR rates were also very high in the triple therapy groups in these studies (79% and 75% in PROVE1 and PROVE2, respectively), again illustrating the validity of response-guided therapy for predicting high SVR rates (Jacobson IM, et al, 58th AASLD 2007, Abstract 177; Hezode C, et al, 58th AASLD 2007, Abstract 80; Kieffer T, et al, 58th AASLD 2007, Abstract LB8).
Figure 3-9: Telaprevir + PEGASYS + COPEGUS show high rates of SVR
Balapiravir (R1626; Roche)
In a Phase 2a study, the triple combination of the HCV RNA polymerase inhibitor balapiravir with PEGASYS® plus ribavirin resulted in a robust synergistic antiviral effect. Neutropenia was a common side effect, thus studies are underway to investigate different dosing regimens in order to maximise efficacy whilst minimising adverse events (Pockros PJ, et al, 58th AASLD 2007, Abstract 167). More recent data show that overall, 84% of patients in the TRIPLE-1500 mg balapiravir plus standard of care arm achieved an SVR with 48 weeks of therapy compared with 65% for patients receiving the standard of care alone (PEGASYS® plus ribavirin). Furthermore, balapiravir-associated hematological abnormalities were found to be reversible (Nelson D, et al, 43rd EASL 2008, Abstract # 993). Use of balapiravir is also associated with a high barrier against the development of resistance to this novel molecule (Le Pogam S, et al. 58th AASLD 2007; Abstract 1298; Le Pogam S, et al, 43rd EASL 2008, Abstract #21).
Figure 3-10: Virological response
The evolution in HCV treatment is continuing with the development of several other novel molecules. For instance, the class of non-nucleoside polymerase inhibitors includes HCV-796 (ViroPharma/Wyeth), GS-9190 (Gilead), PF-868,554 (Pfizer), VCH-759 (Virochem) and A-837093 (Abbott) – all of which are in the preclinical or Phase I stage of development. Meanwhile, the class of protease inhibitors currently includes Celuprevir (BILN-2061; Boehringer), Boceprevir (SCH503034; Schering), Telaprevir (VX950; Vertex/J&J), ITMN-191 (Intermune/Roche) and TMC435350 (Tibotec/Medivir – which are being investigated in Phase I or II studies.
PEGASYS® delivers plasma concentrations that are sustained beyond the dosing period, protecting against viral rebound and maximizing the chance for success. PEGASYS®, rather than pegylated interferon alfa-2b (12KD), is today the preferred partner for the most promising new treatment combinations.
Studies with Schering Plough’s drug SCH503034 with pegylated interferon alfa-2b (12KD) has shown viral rebound 2–4 days after administration. This can lead to viral resistance.
Figure 3-11: New Molecules: intraweek viral rebound with peg-IFN alfa-2b plus SCH 503034
In this multicentre, open-label study, genotype 1 non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin were randomised to pegylated interferon alfa-2b (12KD) alone (n=22), pegylated interferon alfa-2b (12KD) + SCH 503034 200 mg TID (n=12) or pegylated interferon alfa-2b (12KD) + SCH 503034 400 mg TID (n=12).1 Viral rebound was seen before the end of the once-weekly dosing interval. Diminished antiviral activity can lead to the emergence of resistance.2
1. Zeuzem S, et al. 56th AASLD 2005; Abstract 201
2. Havlir D, et al. JAMA 2000; 283: 229